Of Mice, Monitors, and Medicine
Thanks to new technologies and applications of familiar technologies, mice that look normal but carry subtle mutations are being monitored at ORNL in the same ways as hospital patients. These monitoring technologies are helping biologists rapidly identify which mice have a particular mutation, saving time and money and producing interesting scientific results.
ORNL researchers are developing techniques to monitor the health and behavior of mice to determine the genetic changes affecting the experimental animals. Kevin Behel (left), a graduate student from the University of Tennessee, and ORNL's Mike Paulus recently scanned this live mouse using the MicroCAT prototype.
The MicroCAT provides three-dimensional images with 10 times the resolution of systems used today.
Three-dimensional images show the fat deposits and skeleton of a mouse born with an obesity gene.
ORNL is home to one of the world’s largest experimental mouse colonies. This DOE user facility currently houses more than 70,000 mice representing about 400 mutant strains. A mutant strain is produced by altering or eliminating at least one gene in parent mice through radiation, chemical mutagens, or genetic reengineering. A mutant strain could be a model for a human disease if each mouse’s disorder is due to a change in or deletion of a gene that has a counterpart gene in humans with a similar disorder.
One new technology that is impressing research biologists is the MicroCAT system developed in ORNL’s Instrumentation and Controls (I&C) Division by a team led by Mike Paulus and Hamed Sari-Sarraf. This ultra-high-resolution imaging tool generates three-dimensional images with over 10 times the resolution of conventional X-ray-computed tomography systems.
“Thanks to new high-resolution X-ray detectors on the market and the fact that only low-energy X-rays are needed for small animals, we get very sharp, high-contrast images of the internal organs and tissues of mice,” Paulus says. As a result, the MicroCAT shows promise for detecting concealed mutations or signs of disease in mice, such as skeletal defects, abnormally shaped organs, and tumors. The MicroCAT system has been used to study mice with various conditions, including polycystic kidney disease (PKD), which can cause high blood pressure, kidney failure, and premature death in children. Both people and mice born with PKD have an abnormal kidney gene (first identified in mice at ORNL). ORNL’s research biologists had been using manual, time-consuming techniques to confirm that mice believed to be born with PKD as a result of genetic reengineering are developing the disease.
“Now, we bring our mice to Mike Paulus and he scans one every five minutes with the MicroCAT,” says Dabney Johnson, head of the Mammalian Genetics Section of ORNL’s Life Sciences Division. “For some mice, he gets images that show fluid-filled cysts inside their kidneys. If these mice die early, his results suggest that PKD was the cause.”
MicroCAT is also used to study mice that are fat. “Like people, fat mice can have fat deposits in different places,” Johnson says. “But we have identified an obesity gene that causes mice with the gene to have fat deposits in known regions of the body. In the past, we would sacrifice fat mice and dissect each one to determine which fat pads are oversized.”
Now, using MicroCAT, Paulus can image a mouse’s soft tissue, and with the help of an algorithm, compute the tissue’s volume-to-density ratio to locate the fat pads. If the final image shows abnormally large fat deposits, the mouse has the obesity gene. Studies of mice with this gene could help scientists find treatments for obesity in humans.
“By using the MicroCAT,” Johnson says, “we won’t have to rely only on visible genetic mutations and physical examinations to detect mutations. We won’t have to dissect the mouse to study internal organs. We are looking forward to having our own MicroCAT system in our biology laboratories next year.”
Johnson is also looking forward to using another ORNL-developed technology—a sensor system surgically implanted under the skin of a mouse’s neck that measures several physiological indicators in the mouse. The sensor data are transmitted periodically by radiofrequency (rf) signals to a local receiver for display on a computer and analysis by a geneticist. Nance Ericson of the I&C Division, who leads the implant development team, has shown that the miniaturized instrument can measure body temperature, pulse rate, and activity in mice. He plans to add multiple rf receivers to provide triangulation, so biologists can track changes in the position of a mouse in its cage. Johnson plans to use the implanted sensor system for round-the-clock physiological monitoring of certain mice to determine their patterns of activity and sleep.
“Some of our mutant mice born with a pink coat color because of the deletion of a gene may also be missing a nearby gene that codes for a brain protein,” Johnson says. “As a result, they may have a disease found in humans—Angelman syndrome.” Common characteristics of people afflicted with this disorder are an abnormal gait, lower activity level, mental retardation, an inability to verbalize thoughts, and a biorhythm problem that makes it difficult for them to sleep.
Johnson hopes that use of the rf activity sensor will allow biologists to identify mice that have low activity levels and odd sleep patterns that could be linked to Angelman syndrome. Studies of mice known to have Angelman syndrome may lead to a remedy to help people with the disease.
Another way to detect hidden mutations and disease indicators in mice is to analyze their blood and urine, a common practice for assessing human health. Gary Sega of ORNL’s Chemical and Analytical Sciences Division is using gas chromatography/mass spectroscopy (GC/MS) to analyze mouse blood and urine for unusual concentrations of biochemicals and toxic metabolic products. One finding has been particularly valuable.
Some mutant mice at ORNL may have a genetic disease that also afflicts humans—hereditary tyrosinemia. Normal mice and humans break down tyrosine, an amino acid available in food, thanks to the action of a gene (identified at ORNL in mouse DNA). But people and mice with the disease lack this gene’s protein product, which is needed to carry out one step of the metabolic process; as a result, a biochemical product that is not broken down builds up to a toxic level, poisoning the liver. People with the disease are put on a tyrosine-free diet.
Now, ORNL has a way of identifying the mutant mice that have hereditary tyrosinemia. Through GC/MS analysis of mouse body fluids, Sega has identified high concentrations of the liver-destroying toxic product in some mice, indicating they have the disease. This toxic product was found to have the same chemical composition as the one produced in humans with tyrosinemia disease. “By studying mice with this disease,” Johnson says, “we may get insights into how to combat it in humans.”
ORNL monitoring technologies for mice should help researchers more rapidly determine the functions of genes that are found in both mice and humans. By determining which proteins are produced by these genes and what they do in the body, scientists can then work to determine the structure of these proteins and develop drugs based on this information. Thanks to technologies that monitor mice, we may soon be seeing advances in medicine.
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